Compounds useful for preparing an α,α&#39;-diaminoalcohol

ABSTRACT

A process for the manufacture of the α,α&#39;-diaminoalcohol of formula ##STR1## is via N-protected L-phenylalanine lower alkyl esters, corresponding N-protected α-amino-α&#39;-haloketones, and α-amino-α&#39;-haloalcohols.

This is a continuation divisional of application Ser. No. 08/900,413,filed on Jul. 25, 1997, now U.S. Pat. No. 5,847,144 which is adivisional of application Ser. No. 08/718,109, filed Sep. 18, 1996, nowU.S. Pat. No. 5,684,176, which is a Rule 60 divisional of Ser. No.08/514,329, filed Aug. 11, 1995, now U.S. Pat. No. 5,591,885.

BACKGROUND OF THE INVENTION

1. Field

The present invention is concerned with a novel process andintermediates for the manufacture of an α,α'-diaminoalcohol.

2. Description

The compound2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamideof the formula ##STR2## is specifically described in Example 1 ofEuropean Patent Publication 0432695 and in corresponding U.S. Pat. No.5,196,438, the contents of which are herein incorporated by reference,and is a valuable intermediate for the manufacture of thepharmacologically active compounds described in these patents. Thecompound of formula I can be converted as described in Examples 1 and 3of the identified publications into pharmacologically active compoundssuitable for treatment of viral infections, and especially infectionscaused by HIV and other retroviruses.

SUMMARY OF THE INVENTION

The present invention provides a process for the manufacture of2-[3(S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamideof the formula ##STR3## and includes the novel intermediates generatedtherein.

The subject process comprises reacting an L-phenylalanine lower alkylester with a chloroformic acid ester of the formula ClCOOR¹, wherein R¹is lower alkyl, benzyl, or phenyl, to produce a diester of formula##STR4## wherein R is lower alkyl and R¹ is defined as above.

The resulting diester of the formula II is reacted with halogenatedmethyllithium to produce a halogenated α-aminoketone of formula ##STR5##wherein X is halogen and R¹ is defined as above.

The resulting halogenated α-aminoketone of formula III is then reducedto produce a halogenated α-amino catechol of formula ##STR6## wherein Xand R¹ are as defined above.

The resulting halogenated α-aminoalcohol of the formula IV is thencyclized with a base to produce an[(S)-1-[(S)-oxiran-2-yl]-2-phenyl-ethyl]-carbamic acid ester of formula##STR7## wherein R¹ is as defined above.

The resulting [(S)-1-[(S)-oxiran-2-yl]-2-phenyl-ethyl]-carbamic acidester of formula V is then reacted withN-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide offormula ##STR8## to produce a methyl(1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl]-2-hydroxy-propyl]-carbamateof formula ##STR9##

The resulting methyl(1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl]-2-hydroxy-propyl]-carbamateof formula VII is then treated with a base to produce the2-[3(S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamideof formula I.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in terms of its preferredembodiments. These embodiments are set forth to aid in understanding theinvention, but are not to be construed as limiting.

The process in accordance with the invention comprises

a) reacting a L-phenylalanine lower-alkyl ester with a chloroformic acidester of the formula ClCOOR¹, wherein R¹ is lower alkyl, benzyl orphenyl,

b) reacting a resulting diester of the formula ##STR10## wherein R islower alkyl and R¹ has the above significance, with halogenatedmethyllithium,

c) reducing a resulting halogenated α-aminoketone of the formula##STR11## wherein X is halogen and R¹ has the above significance, d)cyclizing a resulting halogenated α-aminoalcohol of the formula##STR12## wherein X and R¹ have the above significance, with a base, e)reacting a resulting [(S)-1-[(S)-oxiran-2-yl]-2-phenyl-ethyl]-carbamicacid ester of the formula ##STR13## wherein R¹ has the abovesignificance, with N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR14## and f) treating the resultingmethyl(1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl]-2-hydroxy-propyl]-carbamateof the formula ##STR15## with a base.

The term "lower alkyl" used above refers to straight-chain or branchedsaturated hydrocarbon residues with 1-8, preferably 1-4, carbon atomssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec.butyl, tert.butyl, pentyl, hexyl, heptyl, octyl, and the like.Halogen denotes bromine, chlorine, fluorine, or iodine.

The diesters of formula II are obtained according to known methods byheating L-phenylalanine with thionyl chloride in a lower alkanol such asmethanol, evaporating the lower alkanol and reacting the resultingL-phenylalanine lower alkyl ester with a chloroformic acid esterClCOOR¹, wherein R¹ signifies lower alkyl, for example, methyl or ethyl,benzyl, or phenyl, in a solvent such as a ketone, for example, methylethyl ketone, or an ether, for example, tert.butyl methyl ether, or ahydrocarbon, preferably toluene, in the presence of a base such as alower alkylamine or an alkali or alkaline earth metal hydroxide,preferably potassium or sodium hydroxide, in the presence of water, at atemperature of 0°-60° C., preferably at 0°-10° C., at pH 4-10,preferably 6-7.

The halomethylation of the resulting diester II is preferably effectedusing halogenated methyllithium which is generated in situ. The latteris conveniently formed using dihalogenated methane, preferably usingbromochloromethane, and a lower alkyl-lithium, preferably butyllithiumor hexyllithium, in an ether, preferably tetrahydrofuran, at -20° to-120° C., preferably -80° C.

The halomethylation of the diester II to the halogenated α-aminoketoneIII can conveniently be carried out by

a) reacting a diester of the formula ##STR16## wherein R is lower-alkyland R¹ has the above significance, with a lower-alkyl-lithium and anorganochlorosilane of the formula ClSi(R²,R³,R⁴), wherein R², R³ and R⁴are lower alkyl or phenyl, and

b) reacting a silyl-protected compound of formula VIII or IX formed asan intermediate ##STR17## wherein R, R¹, R², R³ and R⁴ have the abovesignificance, in the presence of dihalogenated methane and a loweralkyl-lithium.

It has surprisingly been found that the foregoing protection of thecarbamate group present in the diester II by a silyl group with theformation of the compounds of formula VIII or IX above as intermediatesleads to a considerable increase in yield. Butyllithium or hexyllithiumis preferably used as the lower alkyl-lithium and chlorotrimethylsilaneis preferably used as the organochlorosilane ClSi(R²,R³,R⁴). Moreover,an almost complete conversion can be achieved using significantly lesslower alkyl-lithium and dihalogenated methane.

The reduction of the halomethyl ketone III is conveniently carried outin a solvent such as toluene, tetrahydrofuran or an alcohol, preferablymethanol, ethanol or isopropanol, at a temperature between -30 and 80°C., preferably -15° C. and 50° C., optionally under reduced pressure,using sodium bis(2-methoxy-ethoxy)aluminum hydride, lithium aluminumhydride, lithium aluminum tri-tert.-butoxyhydride, sodium borohydride,tetramethylammonium borohydride or, preferably, using an aluminumtri-alkoxide or lithium aluminum tri-alkoxyhydride. The term "alkoxide"embraces straight-chain or branched-chain saturated hydrocarbon oxideswith 1-8, preferably 3-4, carbon atoms, namely methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl oxide as wellas pentyl, hexyl, heptyl and octyl oxides. The aluminum compounds canhave identical or different alkoxide groups. Aluminum tri-isopropoxideand aluminum tri-sec.-butoxide are especially preferred compounds. Thereagents lithium aluminum tri-tert.-butoxyhydride, aluminumtri-isopropoxide and aluminum tri-sec.-butoxide gave unexpectedly a highstereoselectivity of 95:5 of the (1S,2S) and (1S,2R) isomerichalohydrins IV, which could be crystallized from the reaction mediumin >99% optical purity and with high yield.

The ring closure of the halohydrin of formula IV is conveniently carriedout in a solvent such as ethanol or preferably a toluene/water mixturein the presence of a base such as an alkali or alkaline earth metalhydroxide, preferably sodium or potassium hydroxide, at a temperaturebetween 0° and 80° C., preferably 40-15° C., whereby the epoxide offormula V which is formed need not be purified.

The reaction of the epoxide of formula V with the amide VI isconveniently carried out in a solvent such as a hydrocarbon, forexample, toluene, or a lower alkanol, preferably ethanol, while heatingto the reflux temperature, preferably at 20°-100° C., especially at 80°C.

The cleavage of the N-protecting group from the compound of formula VIIis conveniently effected in a solvent such as water, ethanol or amixture thereof using a base such as sodium or potassium hydroxide whileheating to the reflux temperature, preferably at 20°-100° C., especiallyat 80°.

The compounds of formulas III and IV in which R¹ signifies methyl(namely formulas IIIa and IVa, respectively), especially

methyl (S)-1-benzyl-3-chloro-2-oxopropyl)carbamate and, respectively,

methyl (1S,2S)-(1-benzyl-3-chloro-2-hydroxypropyl)carbamate

as well as the compounds of formulas V and VII in which R¹ signifiesmethyl (namely formulas Va and VIIa, respectively), namely

methyl [(S)-1-[(S)-oxiran-2-yl]-2-phenethyl]carbamate and, respectively,

methyl (1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxypropyl]carbamate,

are novel and as such are encompassed by the present invention. Theinvention likewise embraces the compounds of formulas I, III and IV,which can be obtained by the process described above, as well as the useof the compounds of formulas III and IV for the manufacture of thecompounds of formula I.

The compound of formula VI which is used as the starting material isknown and corresponds to that of formula VII in European PatentPublication 0 432 695 and U.S. Patent No. 5,196,438, the contents ofwhich are herein incorporated by reference.

The following Examples are intended to illustrate the present invention,but are not limiting in any manner.

EXAMPLE 1

160 ml of thionyl chloride were added dropwise to 800 ml of methanol at0° C. Subsequently, the mixture was treated with 330.4 g ofL-phenylalanine and heated to 45° C. for 2.5 hours. The resultingsolution was concentrated completely and the residue was taken up in 1.6l of water and treated at 0° C. with 185 ml of methyl chloroformatewhile holding the pH between 6-7 with 40% sodium hydroxide solution. Thesolution was extracted with toluene, the extracts, after washing withwater, were concentrated and the residue was dried at 45° C./0.1 mbar,there being obtained 474.6 g (100%) of pure methyl(S)-2-methoxycarbonylamino-3-phenyl-propionate. IR (KBr): 3338m (NH),1726s br. (C═O), 1531s (amide II).

EXAMPLE 2

41.7 ml of a 2.6 molar solution of hexyllithium in hexane were addeddropwise at -80° C. to a solution of 9.50 g of methyl(S)-2-methoxycarbonylamino-3-phenyl-propionate and 3.22 ml ofbromochloromethane in 60 ml of tetrahydrofuran. Subsequently, a further2.14 ml of bromochloromethane were added and the mixture was againtreated with 23 ml of hexyllithium solution, a further 1.54 ml ofbromochloromethane were added and the mixture was again treated with 7.7ml of hexyllithium solution. The solution was treated at -80° C. with 15ml of 20% methanolic hydrochloric acid, warmed to 22° and diluted with100 ml of water and 40 ml of tetrahydrofuran. The phases were separated,and the organic phase was washed with saturated sodium chloridesolution, dried and concentrated. The residue was recrystallized from 40ml of ethyl acetate and 160 ml of hexane and the crystallizate wasdried, there being obtained 3.83 g (37%) of pure methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 121°-122° C. IR(KBr): 3336s (NH), 1737s and 1686s (C═O), 1535s (amide II).

EXAMPLE 3

15.4 ml of a 2.6 molar solution of hexyllithium in hexane were addeddropwise at -80° C. to a solution of 9.50 g of methyl(S)-2-methoxycarbonylamino-3-phenyl-propionate in 60 ml oftetrahydrofuran. Subsequently, the mixture was treated with 5.60 ml ofchlorotrimethylsilane. The resulting suspension was stirred and treatedwith 3.22 ml of bromochloromethane. Subsequently, 18.4 ml ofhexyllithium solution were added. The solution was treated at -80° C.with 11 ml of 20% methanolic hydrochloric acid, warmed to 22° anddiluted with 100 ml of water and 40 ml of tetrahydrofuran. The phaseswere separated and the organic phase was washed with saturated sodiumchloride solution, dried and concentrated. The residue wasrecrystallized from ethyl acetate and hexane and the crystallizate wasdried, there being obtained 7.20 g (70%) of pure methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 122°-123° C. IR(KBr): 3336s (NH), 1737s and 1686s (C═O), 1535s (amide II).

EXAMPLE 4

A)

33.06 g of lithium aluminum tri-tert.-butoxyhydride were addedportionwise at -15° C. to a suspension of 25.57 g of methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate in 280 ml of ethanol andthe mixture was subsequently hydrolyzed at 0° C. with 140 ml of 3Nhydrochloric acid and 170 ml of water. The suspension was concentratedto 370 ml, filtered and the residue was washed with water/ethanol (4:1)and dried, there being obtained 23.27 g (90%) of isomerically-puremethyl (1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p.163°-164.5° C. IR (KBr): 3323s, br. (NH, OH), 1689 (C═O), 1546s (amideII).

B)

25.57 g of methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate wereadded portionwise at 22° C. to a suspension of 21.44 g of aluminumisopropoxide in 260 ml of isopropanol. The suspension was stirred at 50°C./400 mbar for 2 hours, hydrolyzed at 0° C. with 100 ml of 3Nhydrochloric acid, subsequently concentrated to a volume of 125 ml,diluted with 125 ml of water, cooled to 0° C. and filtered. The residuewas washed with water/isopropanol (4:1) and dried, there being obtained13.01 g (89%) of isomerically-pure methyl (1S,2S)-(1-benzyl-3-chloro2-hydroxy-propyl)-carbamate, m.p. 162°-163.5° C. IR (KBr): 3323s, br.(NH, OH), 1689 (C═O), 1546s (amide II).

EXAMPLE 5

3.75 g of sodium borohydride were added portionwise at -15° C. to asuspension of 46.03 g of methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate in 275 ml of methanol.The mixture was stirred for 1.5 hours, diluted with 21 ml of acetic acidand 460 ml of water, stirred at -15° C. for 1 hour and filtered. Theresidue was washed with water, recrystallized from 430 ml of isopropanoland the crystallizate was dried, there being obtained 28.68 g (62%) of a98:2 mixture of the (1S,2S):(1S,2R)-isomers of methyl(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p. 161.5°-162.5° C. IR(KBr): 3323s, br. (NH, OH), 1689s (C═O), 1546s (amide II).

EXAMPLE 6

A mixture of 28.35 g of methyl(1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, 8.8 g of sodiumhydroxide, 110 ml of toluene and 110 ml of water was stirred at 40° C.and the organic phase was then washed with water and concentrated. Theresidual methyl [(S)-1-[(S)-oxiran-2-yl]-2-phenyl-ethyl]-carbamate wastaken up in 130 ml of ethanol, treated with 26.22 g ofN-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide andheated at reflux for 5.3 hours. The suspension was diluted with 80 ml ofwater, cooled to 22° and filtered, and the residue was washed with a 1:1mixture of ethanol/water and dried, there being obtained 46.30 g (92%)of methyl(1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxy-propyl]-carbamate,m.p. 19°-195° C. IR (KBr): 3411m and 3317m (NH, OH), 1715s and 1659s(C═O), 1548s (amide II).

EXAMPLE 7

A suspension of 41.37 g of methyl(1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxy-propyl]-carbamateand 23.0 g of sodium hydroxide in 90 ml of ethanol and 90 ml of waterwas heated at reflux for 3.5 hours, diluted with 45 ml of water andcooled to 22° , and the separated solid was filtered off, washed with a1:4 mixture of ethanol/water and dried, there being obtained 35.35 g(98%) of pure2-[3(S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide,m.p. 173°-175° C. IR (KBr): 3435m, br. (NH, OH), 1665s (C═O), 1562m(amide II).

Upon reading the present specification, various alternative embodimentswill become obvious to the skilled artisan. These variations are to beconsidered within the scope and spirit of the present invention which isonly to be limited by the claims which follow and their reasonableequivalents.

What is claimed is:
 1. A compound of formula ##STR18## wherein X ishalogen and R¹ is methyl.
 2. The compound of claim 1 which ismethyl(S)-1-benzyl-3-chloro-2-oxopropyl)carbamate.
 3. A compound offormula ##STR19## wherein X is halogen and R¹ is methyl.
 4. The compoundof claim 3 which ismethyl(1S,2S)-(1-benzyl-3-chloro-2-hydroxypropyl)carbamate.
 5. Acompound of formula ##STR20## wherein R¹ is methyl.